This application proposes transitional support for Dr Dimitrios Spentzos, a junior investigator who completed a productive mentored post doctoral training in cancer genomics, and recently assumed an independent translational appointment with a clinical focus in sarcoma. Sarcoma is a disease with a substantial clinical and biologic complexity and high incidence in younger populations, the molecular underpinnings of which are poorly understood. Preliminary data generated by the applicant using advanced computational methods of analyzing multiple publicly available sarcoma microarray datasets, generated testable hypotheses on improved molecular classification of sarcoma with relevance to outcome and targeted therapeutics. In Specific aim 1, the applicant proposes study a previously discovered molecular diagnostic profile in a large tumor cohort, hypothesizing that it will capture the heterogeneity of sarcomas better than traditional histologic classification. In addition, he proposes a novel classification scheme based on simultaneous assessment of activation status of several pathways using expression profiling, and intends to test its association with outcome and response to therapy. These pathways are all targeted by inhibitors that are already in clinical trials albeit without the means to prioritize appropriate patients for their study, thus this work provides the basis for future personalized therapy and rational targeted drug development. In Aims 2 and 3 the applicant will extend his work to the microRNA level and will test the relationship of microRNA activation or expression levels, with gene expression, oncogenic pathways, and outcome in human soft tissue sarcoma and osteosarcoma, thus further elucidating the molecular context of this disease in a manner that allows optimal therapeutic strategies to emerge. Advanced computational methods will be used, based on the candidate's exceptional training on medical applications of computational biology. Also, based on solid preliminary feasibility data, paraffin sarcoma tissue will be used for this study in order to increase access to large unselected cohorts, and the chance of larger validation and future clinical application of discoveries. This proposal and the training will serve the future career goals of the applicant, to become a leader in translational genomics and Systems Biology cancer investigation, with a clinical focus in sarcoma. He will benefit from the superb cancer research environment available to him at Harvard Medical School, Beth Israel Deaconess Medical Center and Dana/Farber Harvard Cancer Center, and from the expertise of senior advisors in both the genomics and sarcoma fields, aw well as the critical collaborative relationships that he will develop with the support of this Award, and the educational and scientific opportunities within the Systems Biology Department at Harvard Medical School. In the immediate future, this Award will provide critical support for him to establish a research program in a new disease focus that will be competitive for independent NIH-level support in the next 2-3 years. PUBLIC HEALTH RELEVANCE: Sarcomas are cancers with almost unparalleled clinical, biologic and molecular diversity that disproportionately affect young adults or children. Despite their complexity, classification and therapeutic approaches, with rare exceptions, have not advanced in almost 20 years. This grant proposal will utilize cutting-edge tools of tumor genomic analysis to dissect their molecular complexity so that novel personalized therapies can be developed.